Venous thromboembolism (VTE) is a major health problem. The recent Surgeon General's Call to Action identified the reasons for the persistent occurrence of VTE as critical barriers to progress in the field. This project will address this question at the population level and shift clinical practice paradigms for primary and secondary VTE prevention by development and validating risk prediction tools to target specific subsets of high VTE-risk individuals. Our specific aims will address current gaps in knowledge by: (Aim 1) estimating (1a) secular trends in (i) VTE incidence and attack (incident and recurrent VTE) rates, (ii) prevalence and (iii) population attributable risk for each VTE risk factor, and (1b) estimating (i) transition probabilities in a multi-state model for incident and recurrent VTE and death after VTE and (ii) trends in survival after VTE to help inform public policy; (Aim 2) derivin and validating an overall VTE recurrence prediction score, including germline genetic variation (F5 rs6025, F2 rs1799963, ABO rs8176719); and (Aim 3) deriving and validating risk and prediction scores for (a) incident and (b) recurrent VTE among active cancer patients, respectively, including plasma biomarkers, germline genetic variation, and cancer tissue procoagulant (tissue factor) antigen expression for both scores. We will use data from previously completed case-control and case-cohort studies to derive the risk and prediction scores, and the longitudinal resources of the Rochester Epidemiology Project and the Mayo Clinic Cancer Registry to perform cohort studies of the entire population of Olmsted County and a large cohort of active cancer patients, respectively, for validation of the scores. The ability t identify high-risk subsets of individuals within: a) the general population (Aim 1), b) those with an incident VTE (aim 2), and c) those with active cancer (Aim 3) will facilitate targeted primary and secondary VTE prevention in a cost-effective and safe manner.